As we already covered before, 2016 shows a lot of promise to be a great year for life extension research. One of the most interesting studies planned for this year is the TAME trial[1] (Targeting Aging with Metformin), a study that will test the use of aforementioned compound as a longevity drug in older adults who have cancer, heart disease, or cognitive impairment (or are at risk for these diseases).

What is it, exactly?

Metformin 3D structure

Metformin, also known as Glucophage ®, is an anti-diabetic drug that works by suppressing glucose production in the liver. Unlike the majority of diabetes drugs, however, it does not cause hypoglycemia (low blood sugar), even when given to non-diabetics.

Metformin is a drug of the biguanide class. As such, it resembles the compounds guanidine and galegine, found in the Galega officinalis plant (aka goat’s rue). Goat’s rue was known to have anti-diabetic activity since ancient times, but it proved too toxic to use.

The beginning of the history of metformin, however, has almost nothing to do with type 2 diabetes, but with an even worse disease: malaria.

History of Metformin

Harvested bark of Cinchona officinalis

Malaria is a disease caused by a parasitic microorganism of the Plasmodium species. The typical treatment for malaria before the advent of synthetic drugs was quinine, an alkaloid extracted from the bark of the South American tree Cinchona officinalis.

Quinine was expensive, and some parasites became resistant to it. Furthermore, the drug was imported from Java and the supply was unpredictable. In the 1930s, researchers began to discover and synthesize alternatives to quinine. A chemist named Francis H. S. Curd started investigating pyrimidine analogs at the ICI laboratories at Blackley, Manchester, after he noticed that some drugs with mild antimalarial activity had a pyrimidine ring in their structure.

Goat’s rue

A number of compounds were synthesized and tested on malaria-infected chicks. Some of them were also tested on humans, but they proved too toxic for clinical use. Nonetheless, Curd persisted on in his research, and he figured out that using only a portion of the pyrimidine structure could potentially minimize toxicity while maximizing antimalarial effects. Paludrine, the fruit of Curd’s successful hypothesis, was synthesized in 1945. It is also interesting to note that part of Paludrine’s structure closely resembled galegine, the active component in goat’s rue mentioned above. Animal studies conducted two years after Paludrine’s discovery established that it was able to cause a small decrease in blood glucose. At the same time, in the Philippines, molecules of the same biguanide class were used by Dr. Eusebio Garcia, a local expert in infectious diseases. He noticed that flumamine, a guanidine analog, cured malaria in addition to lowering blood sugar levels.

The real breakthrough came with the work of French diabetologist Jean Sterne. While working at Aron Laboratories in Paris, he was prompted to action by Garcia’s report on flumamine. In collaboration with Denise Duval and others, he evaluated the anti-diabetic effect of flumamine in animals. It showed a powerful glucose-lowering effect which led him to coin the name Glucophage ®, meaning “glucose eater”. He published his results in 1957.[2]

Flumamine eventually became metformin and, in 1962, the first major clinical trial that tested metformin’s efficacy intype 2 diabetes was published.[3] 39 subjects were involved in the study, with almost all of them being over 30 years old. The study came to the following conclusions:

of the 39 patients, 14 showed satisfactory control of the disease with metformin

another 6 showed some improvement if the metformin was combined with low-dose insulin or another oral anti-diabetic agent

‘pancreatic’ diabetics (now known as type 1 diabetes) did not respond to the treatment

treatment was with 1–3 grams of metformin per day, given as three divided doses, titrating up slowly and limited by the emergence of certain side effects.

Metformin was not the only biguanide anti-diabetic discovered in the 1930s. Phenformin and Buformin, used respectively in America and Europe, were actually stronger in anti-diabetic activity and had been the drugs of choice for type 2 diabetes up until the 70s, when they were banned after an ever-increasing number of deaths by lactic acidosis. Because metformin was seen as closely related to these two drugs, metformin’s public image was damaged. Although metformin hardly ever causes lactic acidosis, its damaged reputation meant it would take longer to catch on.

The next few decades saw a steady accumulation of data concerning metformin’s effectiveness and safety. One study, in particular, helped establish Glucophage ® as a safe and effective treatment for diabetes. The United Kingdom Prospective Diabetes Study, conducted from 1977 through 1997, effectively gave scientific evidence that metformin increases the lifespan of patients with obesity and type 2 diabetes.[4] Patients treated with metformin also had less incidence of heart attacks when compared to those treated with insulin or other diabetes drugs.

The Food and Drug Administration (FDA) of the United States approved metformin in 1994, which prompted its ascent as a popular diabetes drug in America. The patents covering metformin expired in 2002, which allowed it to be produced and sold inexpensively as a generic drug.[5]

New uses for an old drug

Cancer

Even though the research on Metformin as a cancer prevention tool is still in its infancy, it appears to be very promising. Metformin and other biguanide medications have been increasingly investigated for their chemopreventive (cancer-preventive) and antineoplastic (tumor growth-inhibiting) properties. There have been various studies conducted on lab animals that investigate metformin’s ability to reverse or prevent tumor growth. One meta-analysis on the subject reported that metformin’s effects on cancer have been tested on 17 different organs in various strains of rats, mice, and hamsters. Some studies investigated its effects on naturally-occurring cancer while others investigated how it affected cancer induced in the lab by 16 different chemical classes of carcinogens. In other words, metformin’s anticancer effects were studied under a wide variety of unique and nuanced cases of tumor growth. Many different dosing regimens and routes of administration were also tested.[6] In the majority of cases (86%) the treatment with metformin and other biguanides led to inhibition of carcinogenesis. No cases of stimulation of carcinogenesis by the antidiabetic biguanides were ever detected.

While the mechanism of action for the chemopreventive activity of Metformin is not entirely clear, it is likely caused by the activation of AMPK-dependent and AMPK-independent pathways, in addition to energy metabolism aberration, cell cycle arrest, apoptosis or autophagy induction,[7] as well as mTOR signaling inhibition.[8]

Life Extension

In April of 2003, researchers at Biomarker Pharmaceuticals in California studied the effects of metformin on aging processes and longevity. The researchers found that metformin actually mimics the anti-aging effects of caloric restriction. Caloric restriction is a type of dietary method that involves consuming a significantly reduced amount of calories while still consuming proper amounts of essential vitamins and nutrients. This method has been touted by some to slow the aging process and extend lifespan. When tested on mice, metformin appears to induce a change in gene expression that is identical to that caused by a CR diet. This change in gene expression has the potential to extend animal life spans by 20 percent. Metformin is the first medication that has been discovered to mimic the effects of a CR-induced lifespan extension.[9]

Another study published in the AGING Journal showed that female mice treated with metformin from an early age lived longer and had fewer tumors. These effects were not seen in aged mice[10]

Contraindications and Side effects

Metformin is a relatively safe drug. As said before, it can be taken by non-diabetics as long as the dose does not exceed 1500-1700 mg. A good idea is to check blood glucose levels. It’s not advised to take Glucophage ® should the blood glucose levels be equal or lower than 80mg/dL.

Metformin should not be used in those with liver disease, kidney problems or lung disease, and any other condition that could increase the risk of lactic acidosis.

Long-term use of high doses of Metformin may cause Vitamin B12 deficiency[11], especially in those who do not consume animal products (vegetarians and vegans). The amount of B12 in a multivitamin is generally not enough to correct the deficiency[12]. It is therefore a good idea to supplement Vitamin B12 when taking Metformin.

The most common adverse effect are related to the gastrointestinal system, and may include diarrhea, cramps, nausea, vomiting, and increased flatulence. To avoid these side effects Metformin should be started at the lowest dose (500 mg) and slowly increased to the desired dose.

Conclusion

Metformin has been a revolutionary drug for diabetes, and new research on biguanides shows that these drugs may enhance lifespan as well as prevent cancer. While it’s still a bit early to recommend metformin to every >50 years old, (or subjects in high-risk populations, like smokers), we’re finally getting closer to a real breakthrough in life extension research.

More research is needed in order to understand the correct dosage and efficacy of Metformin in humans.